Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress
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Journal of Psychosomatic Research 53 (2002) 865 – 871
Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress
Constantine Tsigosa,c, George P. Chrousosb,c,*
a
Hellenic National Diabetes Center, Athens, Greece
b
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health,
Bldg. 10, Rm. 9D42, Bethesda, MD 20892-1583, USA
c
Athens University Medical School, Athens, Greece
Abstract
The stress system coordinates the adaptive responses of the limbic dopaminergic system and the CRH peptidergic central
organism to stressors of any kind.1 The main components of the nucleus of the amygdala. In addition, they directly inhibit pituitary
stress system are the corticotropin-releasing hormone (CRH) and gonadotropin, GH and TSH secretion, render the target tissues of
locus ceruleus – norepinephrine (LC/NE)-autonomic systems and sex steroids and growth factors resistant to these substances and
their peripheral effectors, the pituitary – adrenal axis, and the limbs suppress the 50 deiodinase, which converts the relatively inactive
of the autonomic system. Activation of the stress system leads to tetraiodothyronine (T4) to triiodothyronine (T3), contributing
behavioral and peripheral changes that improve the ability of the further to the suppression of reproductive, growth and thyroid
organism to adjust homeostasis and increase its chances for functions. They also have direct as well as insulin-mediated effects
survival. The CRH and LC/NE systems stimulate arousal and on adipose tissue, ultimately promoting visceral adiposity, insulin
attention, as well as the mesocorticolimbic dopaminergic system, resistance, dyslipidemia and hypertension (metabolic syndrome X)
which is involved in anticipatory and reward phenomena, and the and direct effects on the bone, causing ‘‘low turnover’’
hypothalamic b-endorphin system, which suppresses pain sensa- osteoporosis. Central CRH, via glucocorticoids and catechol-
tion and, hence, increases analgesia. CRH inhibits appetite and amines, inhibits the inflammatory reaction, while directly secreted
activates thermogenesis via the catecholaminergic system. Also, by peripheral nerves CRH stimulates local inflammation (immune
reciprocal interactions exist between the amygdala and the CRH). CRH antagonists may be useful in human pathologic
hippocampus and the stress system, which stimulates these states, such as melancholic depression and chronic anxiety,
elements and is regulated by them. CRH plays an important role associated with chronic hyperactivity of the stress system, along
in inhibiting GnRH secretion during stress, while, via somatosta- with predictable behavioral, neuroendocrine, metabolic and
tin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, immune changes, based on the interrelations outlined above.
the reproductive, growth and thyroid functions. Interestingly, all Conversely, potentiators of CRH secretion/action may be useful to
three of these functions receive and depend on positive treat atypical depression, postpartum depression and the fibro-
catecholaminergic input. The end-hormones of the hypothala- myalgia/chronic fatigue syndromes, all characterized by low HPA
mic – pituitary – adrenal (HPA) axis, glucocorticoids, on the other axis and LC/NE activity, fatigue, depressive symptomatology,
hand, have multiple roles. They simultaneously inhibit the CRH, hyperalgesia and increased immune/inflammatory responses to
LC/NE and b-endorphin systems and stimulate the mesocortico- stimuli. D 2002 Elsevier Science Inc. All rights reserved.
Keywords: Stress; Glucocorticoids; Corticotropin-releasing hormone or factor (CRH or CRF)
* Corresponding author. Tel.: +1-301-496-5800; fax: +1-301-402-0884. Physiology of the stress response
E-mail address: chrousog@mail.nih.gov (G.P. Chrousos).
1
‘‘Stress’’ is defined as a state of disharmony or threatened homeo-
stasis. The concepts of stress and homeostasis can be traced back to ancient
Life exists by maintaining a complex dynamic equilib-
Greek history, however, the integration of these notions with related rium or homeostasis that is constantly challenged by
physiologic and pathophysiologic mechanisms and their association with intrinsic or extrinsic adverse forces, the stressors [1]. Under
specific illnesses are much more recent. favorable conditions, individuals can be invested in veget-
In the present overview, we focus on the cellular and molecular ative and pleasurable functions that enhance their emotional
infrastructure of the physiologic and behavioral adaptive responses to stress
and we define the pathophysiologic effects of the dysregulation of the stress
and intellectual growth and development and the survival of
response, which may result in vulnerability to several disease entities, such their species, such as food intake and sex. In contrast,
as anxiety or depression and chronic inflammatory processes. activation of the stress response during threatening situa-
0022-3999/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved.
PII: S 0 0 2 2 - 3 9 9 9 ( 0 2 ) 0 0 4 2 9 - 4866 C. Tsigos, G.P. Chrousos / Journal of Psychosomatic Research 53 (2002) 865–871
tions that are beyond the control of the individual can be ent sympathetic/adrenomedullary system, represent the
associated with dysphoria and eventually emotional or effector limbs, via which the brain influences all body
somatic disease [2,3]. organs during exposure to threatening stimuli (Fig. 1)
When faced with excessive stress, whether physical or [6,7]. The brain also differentially activates a subset of
emotional, a subject’s adaptive responses attain a rel- vagal and sacral parasympathetic efferents that mediate the
atively stereotypic nonspecific nature, referred to by Selye gut responses to stress [8].
as ‘‘the general adaptation syndrome.’’ We now know that There are mutual interactions of the central stress stations
the adaptive responses have some specificity toward the with three higher brain control areas that influence affect
stressor that generates them, which, however, is progres- and anticipatory phenomena (mesocortical/mesolimbic sys-
sively lost as the severity of the stressor increases. During tems); the initiation, propagation and termination of stress
stress, attention is enhanced and the brain focuses on the system activity (amygdala/hippocampus complex); and the
perceived threat. Cardiac output and respiration are accel- setting of the pain sensation (arcuate nucleus) [9 –11].
erated, catabolism is increased and blood flow is redir-
ected to provide the highest perfusion and fuel to the The HPA axis
aroused brain, heart and muscles [1].
The brain circuits that initiate and maintain the stress The hypothalamus controls the secretion of ACTH from
response are illustrated in Fig. 1. The central control stations the anterior pituitary, which, in turn, stimulates the secretion
of the stress system are located in the hypothalamus and the by the adrenal cortex of glucocorticoid hormones, mainly
brain stem and include the parvocellular corticotropin- cortisol in humans. The principal hypothalamic stimulus to
releasing hormone (CRH) and arginine – vasopressin the pituitary – adrenal axis is CRH, a 41 amino acid peptide
(AVP) neurons of the paraventricular nuclei (PVN) of the first isolated in 1981 by W. Vale [12]. AVP is a potent
hypothalamus, and the locus ceruleus (LC) –norepinephrine synergistic factor with CRH in stimulating ACTH secretion;
system (central sympathetic system) [2,3]. The hypothala- however, AVP has little ACTH secretagogue activity alone
mic – pituitary – adrenal (HPA) axis, together with the effer- [13]. Furthermore, it appears that there is a reciprocal
positive interaction between CRH and AVP at the level of
the hypothalamus, with each neuropeptide stimulating the
secretion of the other.
In nonstressful situations, both CRH and AVP are
secreted in the portal system in a circadian, pulsatile fashion,
with a frequency of about two to three secretory episodes
per hour [14]. Under resting conditions, the amplitude of the
CRH and AVP pulses increase in the early morning hours,
resulting finally in ACTH and cortisol secretory bursts in
the general circulation [15,16]. These diurnal variations are
perturbed by changes in lighting, feeding schedules and
activity and are disrupted by stress.
During acute stress, the amplitude and synchronization of
the CRH and AVP pulsations in the hypophyseal portal
system markedly increases, resulting in increases of ACTH
and cortisol secretory episodes [3]. Depending on the type
of stress, other factors such as AVP of magnocellular neuron
origin, angiotensin II and various cytokines and lipid
mediators of inflammation are secreted and act on hypo-
thalamic, pituitary or adrenal components of the HPA axis,
potentiating its activity [17,18].
Circulating ACTH is the key regulator of glucocorticoid
secretion by the adrenal cortex. Other hormones or cyto-
Fig. 1. A simplified schematic representation of the central and peripheral kines, either originating from the adrenal medulla or com-
components of the stress system, their functional interrelations and their
relations to other central systems involved in the stress response. The CRH/ ing from the systemic circulation, as well as neuronal
AVP neurons and central catecholaminergic neurons of the LC/NE system information from the autonomic innervation of the adrenal
reciprocally innervate and activate each other. The HPA axis is controlled cortex may also participate in the regulation of cortisol
by several feedback loops that tend to normalize the time-integrated secretion [19,20].
secretion of cortisol, yet glucocorticoids stimulate the fear centers in the Glucocorticoids are the final effectors of the HPA axis
amygdala. Activation of the HPA axis leads to suppression of the GH/IGF-
1, LH/testosterone/E2 and TSH/T3 axes; activation of the sympathetic
and participate in the control of whole body homeostasis
system increases IL-6 secretion. Solid lines indicate stimulation; dashed and the organism’s response to stress. They play a key
lines indicate inhibition. (Adapted from Chrousos and Gold [1]). regulatory role on the basal activity of the HPA axis and onC. Tsigos, G.P. Chrousos / Journal of Psychosomatic Research 53 (2002) 865–871 867
the termination of the stress response by acting at extra- Regulation of the stress response
hypothalamic centers, the hypothalamus and the pituitary
gland [21]. The inhibitory glucocorticoid feedback on the The orchestrated interplay of several neurotransmitter
ACTH secretory response acts to limit the duration of the systems in the brain underlies the characteristic phenom-
total tissue exposure to glucocorticoids, thus, minimizing enology of behavioral, endocrine, autonomic and immune
the catabolic, antireproductive and immunosuppressive responses to stress [28]. These transmitters include CRH,
effects of these hormones. AVP, opioid peptides, dopamine and norepinephrine.
Glucocorticoids exert their effects through their ubiquit-
ous cytoplasmic receptors [22,23]. On ligand binding, the CRH/AVP
glucocorticoid receptors translocate into the nucleus, where
they interact as homodimers with specific glucocorticoid Shortly after its isolation, it became apparent that CRH
responsive elements (GREs) within the DNA to activate was implicated in other components of the stress response,
appropriate hormone-responsive genes [23]. The activated such as arousal and autonomic activity. Supportive evidence
receptors also inhibit, through protein – protein interactions, was derived from intracerebroventricular or selective brain
other transcription factors, such as c-jun/c-fos and NF-kB, administration of CRH in rodents and nonhuman primates,
which are positive regulators of the transcription of several which precipitated several coordinated responses character-
genes involved in the activation and growth of immune and istic of stress [29]. Moreover, brain administration of CRH
other cells [24]. Furthermore, glucocorticoids change the peptide antagonists suppresses many aspects of the stress
stability of messenger RNAs and hence the translation of response. Finally, CRH type 1 receptor knockout mice were
several glucocorticoid-responsive proteins, as well as the shown to have a markedly deficient ability to mount an
electrical potential of neuronal cells. effective stress response [30].
CRH and CRH receptors were found in many sites in
The autonomic axes the brain outside of the hypothalamus, including parts of
the limbic system and the central arousal sympathetic
The autonomic nervous system provides a rapidly systems (LC/NE) in the brain stem and spinal cord [31].
responding mechanism to control a wide range of functions Stress is a potent general activator of CRH release from
[3]. Cardiovascular, respiratory, gastrointestinal, renal, the hypothalamus and extrahypothalamic sites [5]. The
endocrine and other systems are regulated by the sympath- mechanisms via which stress stimulates CRH neurons are
etic nervous system or the parasympathetic system, or both unclear. Whether CRH or another transmitter (e.g., NE) is
[25]. Interestingly, the parasympathetic system may assist upstream in eliciting the neurocircuitry of stress remains to
sympathetic functions by withdrawing and can antagonize be determined.
them by increasing its activity. CRH-binding sites are also found in various peripheral
Sympathetic innervation of peripheral organs is derived tissues, such as the adrenal medulla, heart, prostate, gut,
from the efferent preganglionic fibers, whose cell bodies lie liver, kidney and testes. CRH receptors belong to the G-
in the intermediolateral column of the spinal cord. These protein-coupled receptor superfamily, and CRH binding
nerves synapse in the bilateral chains of sympathetic stimulates the intracellular accumulation of cAMP. Two
ganglia with postganglionic sympathetic neurons that richly distinct CRH receptor subtypes designated CRH-R1 and
innervate the smooth muscle of the vasculature, the heart, CRH-R2 have been characterized, encoded by distinct genes
skeletal muscles, kidney, gut, fat and many other organs. that are differentially expressed [31]. CRH-R1 is the most
The preganglionic neurons are cholinergic, whereas the abundant subtype found in the anterior pituitary and is also
postganglionic neurons are mostly noradrenergic. The sym- widely distributed in the brain [32]. CRH-R2 receptors are
pathetic system also has a humoral contribution, providing expressed mainly in the peripheral vasculature and the heart,
most of the circulating epinephrine and some of the as well as in subcortical structures in the brain.
norepinephrine from the adrenal medulla. In addition to
the classic neurotransmitters acetylcholine and norepinephr- LC/NE system
ine, both sympathetic and parasympathetic subdivisions of
the autonomic nervous system contain several subpopula- The locus ceruleus and other noradrenergic cell groups of
tions of target-selective and neurochemically coded neurons the medulla and pons are collectively known as the LC/NE
that express a variety of neuropeptides and, in some cases, system. Brain epinephrine serves globally as an alarm system
ATP, nitric oxide or lipid mediators of inflammation [26]. that decreases neurovegetative functions, such as eating and
Interestingly, CRH, neuropeptide Y (NPY) and somatostatin sleeping, and that contributes to accompanying increases in
are colocalized in noradrenergic vasoconstrictive neurons. autonomic and neuroendocrine responses to stress, including
Transmission in sympathetic ganglia is also modulated by HPA axis activation [28]. NE also activates the amygdala, the
neuropeptides released from preganglionic fibers and short principal brain locus for fear-related behaviors, and enhances
interneurons (e.g., enkephalin and neurotensin), as well as the long-term storage of aversively charged emotional mem-
from primary afferent collaterals (e.g., substance P) [27]. ories in sites such as the hippocampus and striatum.868 C. Tsigos, G.P. Chrousos / Journal of Psychosomatic Research 53 (2002) 865–871
Reciprocal neural connections exist between the CRH The efferent sympathetic/adrenomedullary system appa-
and (LC/NE system neurons) of the central stress system, rently participates in a major fashion in the interactions of
with CRH and norepinephrine stimulating each other, the the HPA axis and the immune/inflammatory reaction by
latter primarily through a1-noradrenergic receptors [3,28]. being reciprocally connected with the CRH system, by
There is an ultra-short autoregulatory negative feedback receiving and transmitting humoral and nervous immune
loop on the CRH neurons exerted by CRH itself, just as signals from the periphery, by densely innervating both
there is a similar loop in the LC/NE neurons, by way of primary and secondary lymphoid organs, and by reaching
presynaptic CRH and a2-noradrenergic receptors, respect- all sites of inflammation via the postganglionic sympathetic
ively. There is also parallel regulation of both central neurons [36]. When activated during stress, the autonomic
components of the stress system by other stimulatory and system exerts its own direct effects on immune organs,
inhibitory neuronal pathways. Several neurotransmitters, which can be immunosuppressive, or both immunopotenti-
including serotonin and acetylcholine, excite CRH and ating and antiinflammatory. CRH secreted by postgan-
the LC/NE neurons [32]. The negative feedback controls, glionic sympathetic neurons at inflammatory sites has
include glucocorticoids, g-amino-butyric acid (GABA), proinflammatory properties (immune CRH); one of its key
corticotropin and several opioid peptides, which inhibit actions is to degranulate mast cells [36,37].
both CRH and LC/NE neurons [33].
HPA axis — other endocrine axes interactions
Body systems responses to stress Gonadal and growth axes
The systems responsible for reproduction and growth are
HPA axis – immune system interactions directly linked to the stress system and both are profoundly
inhibited by various components of the HPA axis, the
It has been known for several decades that stress, effector of the stress response [28,37]. Either directly or
whether inflammatory, traumatic or psychological, is asso- through arcuate POMC neuron b-endorphin, CRH sup-
ciated with concurrent activation of the HPA axis. In the presses the GnRH neurons of the arcuate nucleus of the
early 1990s, it also became apparent that cytokines and hypothalamus. Glucocorticoids exert inhibitory effects at the
other humoral mediators of inflammation are potent activa- levels of the GnRH neuron, the pituitary gonadotroph, and
tors of the central stress response, constituting the afferent the gonads themselves and render target tissues of sex
limb of a feedback loop through which the immune/inflam- steroids resistant to these hormones. Suppression of gonadal
matory system and the CNS communicate [34]. function caused by chronic HPA axis activation has been
All three inflammatory cytokines, tumor necrosis factor- demonstrated in highly trained athletes of both sexes, in
a (TNF-a), interleukin-1b and interleukin-6 (IL-6) can ballet dancers, and in individuals sustaining anorexia nerv-
cause stimulation of the HPA axis alone, or in synergy with osa or starvation.
each other [34,35]. There is evidence to suggest that IL-6, During inflammatory stress, cytokines suppress repro-
the main endocrine cytokine, plays the major role in the ductive function directly and indirectly by activating hypo-
immune stimulation of the axis, especially in chronic thalamic secretion of CRH and POMC-derived peptides, as
inflammatory stress. well as by peripheral elevations of glucocorticoids and
Some of the activating effects of cytokines on the inhibition of steroidogenesis at both ovaries and testes [38].
HPA axis may be exerted indirectly by stimulation of the The interaction between CRH and the gonadal axis
central catecholaminergic pathways. Also, activation of appears to be bidirectional. Thus, the presence of estrogen
peripheral nociceptive, somatosensory and visceral affer- responsive elements has been demonstrated in the promoter
ent fibers would lead to stimulation of both the catecho- area of the CRH gene, as well as direct stimulatory estrogen
laminergic and CRH neuronal systems via ascending effects on CRH gene expression [39]. This finding impli-
spinal pathways. Other inflammatory mediators, such as cates the CRH gene as a potentially important target of
eicosanoids, platelet-activating factor (PAF) and serotonin ovarian steroids and a potential mediator of gender-related
may also participate in the activation of the HPA axis differences in the stress response and HPA axis activity.
[34], via auto/paracrine and/or endocrine effects. The growth axis is also inhibited at many levels during
Conversely, activation of the HPA axis has profound stress. Prolonged activation of the HPA axis with elevations
inhibitory effects on the inflammatory/immune response in glucocorticoids leads to suppression of growth hormone
because virtually all the components of the immune secretion and inhibition of somatomedin C and other growth
response are inhibited by cortisol. Alterations of leuko- hormone effects on their target tissues [40]. However, acute
cyte traffic and function, decreases in production elevations of growth hormone concentration in plasma may
of cytokines and mediators of inflammation, and inhibi- occur at the onset of the stress response or after acute
tion of the latter’s effects on target tissues are among administration of glucocorticoids, presumably through
the main immunosuppressive effects of glucocorticoids stimulation of the GH gene by glucocorticoids through
[34,36]. glucocorticoid-responsive elements in its promoter regionC. Tsigos, G.P. Chrousos / Journal of Psychosomatic Research 53 (2002) 865–871 869
[41]. In addition to the direct effects of glucocorticoids, corticoids induce insulin resistance, activation of the HPA
CRH-induced stimulation in hypothalamic somatostatin axis may contribute to the poor control of diabetic patients
secretion may also result in GH suppression, providing during periods of emotional stress, or concurrently with
another potential mechanism for stress-related suppression inflammatory and other diseases [44].
of GH secretion. Obese subjects with psychiatric manifestations ranging
Similarly, activation of the HPA axis is associated with from those of melancholic depression to anxiety with
decreased production of thyroid-stimulating hormone and perception of ‘‘uncontrollable’’ stress, frequently have mild
inhibition of the conversion of the relatively inactive thyro- hypercortisolism, while carefully screened obese subjects
xin to the more biologically active triiodothyronine in without such manifestations are eucortisolemic [3]. The
peripheral tissues (the ‘‘euthyroid sick’’ syndrome) [42]. former may have stress-induced glucocorticoid-mediated
Both phenomena may be caused by the increased levels of visceral obesity and metabolic syndrome manifestations,
glucocorticoids and may serve to conserve energy during which in the extreme may be called a pseudo-Cushing state
stress. In the case of inflammatory stress, inhibition of TSH that needs to be differentiated from frank Cushing syn-
secretion may be in part through the action of cytokines both drome. Stress-induced hypercortisolism and visceral obesity
on the hypothalamus and the pituitary [35]. and their cardiovascular and other sequelae increase the all-
cause mortality risk of affected subjects by two- to three-
Metabolism fold and curtail their life expectancy by several years [43].
Glucocorticoids directly inhibit pituitary growth hor-
mone, gonadotropin and thyrotropin secretion and make
the target tissues of sex steroids and growth factors resistant HPA axis: pathophysiology
to these hormones. Thus, glucocorticoids antagonize the
beneficial actions of GH and sex steroids on fat tissue Generally, the stress response with the resultant activation
(lipolysis) and muscle and bone anabolism [43]. Chronic of the HPA axis is meant to be acute or at least of a limited
activation of the stress system would be expected to increase duration. The time-limited nature of this process renders its
visceral adiposity, decrease lean body (muscle and bone) accompanying antireproductive, antigrowth, catabolic and
mass and suppress osteoblastic activity (Fig. 2). Interest- immunosuppressive effects temporarily beneficial rather
ingly, the phenotype of central obesity and decreased lean than damaging. In contrast, chronicity of stress system
body mass is shared by patients with Cushing’s syndrome activation would lead to the syndromal state that Selye
and some patients with the combined diagnosis of mel- described in 1936 [4]. Because CRH coordinates behavioral,
ancholic depression or chronic anxiety disorder and the neuroendocrine and autonomic adaptation during stressful
metabolic syndrome (visceral adiposity, insulin resistance, situations, increased and prolonged production of CRH
dyslipidemia, hypertension) or ‘‘pseudo-Cushing’s syn- could explain the pathogenesis of the syndrome [28,45].
drome’’ [43]. The prototypic example of chronic hyperactivation of the
Because increased hepatic gluconeogenesis is a char- stress system (both HPA axis and LC/NE system) is man-
acteristic feature of the stress response and because gluco- ifested in melancholic depression, with dysphoric hyper-
arousal and relative immunosupression [6,7]. Indeed,
cortisol secretion is increased and plasma ACTH response
to exogenous CRH decreased. Hypersecretion of CRH has
been shown in depression and suggests that CRH may
participate in the initiation or perpetuation of a vicious
cycle. Owing to a chronically hyperactive stress system,
patients with melancholic depression may sustain several
severe somatic sequelae, such as osteoporosis, features of
the metabolic syndrome, varying degrees of atherosclerosis,
innate and T-helper 1-directed immunosuppression and
certain infectious and neoplastic diseases [28,43,45]. When
not treated, these patients have a compromised life expect-
ancy curtailed by 15 –20 years after excluding suicides.
In addition to melancholic depression, a spectrum of
other conditions may be associated with increased and
prolonged activation of the HPA axis (Table 1), including
anorexia nervosa with or without malnutrition, obsessive –
compulsive disorder, panic anxiety, chronic active alcohol-
Fig. 2. Detrimental effects of chronic stress on adipose tissue metabolism
ism, alcohol and narcotic withdrawal, excessive exercising,
and bone mass. Solid lines indicate stimulation; dashed lines indicate poorly controlled diabetes mellitus, childhood sexual abuse
inhibition. (Adapted from Chrousos [28]). and hyperthyroidism [1,28,45].870 C. Tsigos, G.P. Chrousos / Journal of Psychosomatic Research 53 (2002) 865–871
Table 1 central hypocortisolism [47]. Dysfunction of the HPA axis
States associated with hyperactivation or hypoactivation of the HPA axis
may actually play a role in the development or perpetuation
Increased HPA Decreased HPA Disrupted HPA of autoimmune disease, rather than being an epiphen-
axis activity axis activity axis activity
omenon. The same rational may explain the high incidence
Severe chronic disease of autoimmune disease in the period after cure of hyper-
Melancholic depression Atypical depression Cushing syndrome
cortisolism, as well as in glucocorticoid underreplaced
Anorexia nervosa Seasonal depression Glucocorticoid
deficiency adrenal insufficiency.
Obsessive – compulsive Chronic fatigue Glucocorticoid
disorder syndrome resistance
Fibromyalgia
Panic disorder Hypothyroidism Future directions
Chronic excessive Adrenal suppression
exercise There has been a long search for small molecular weight
Malnutrition Post glucocorticoid therapy CRH antagonists that could be absorbed orally and cross the
Diabetes mellitus Post stress
blood brain barrier to treat disorders characterized by a
Nicotine withdrawal
Postpartum hyperactive CRH neuron as in melancholic depression.
Hyperthyroidism Menopause Antalarmin, a prototype CRH receptor type 1 antagonist,
Central obesity Rheumatoid arthritis shows that this concept bears merit [5,28]. This small
Childhood sexual pyrrolopyrimidine compound, binds with high affinity to
abuse
the CRH receptor type 1, decreases the activity of the HPA
Pregnancy
axis and LC/NE, blocks the development and expression of
Adapted from Chrousos and Gold [1].
conditioned fear and stress-induced colonic hyperfunction,
suppresses neurogenic inflammation and blocks CRH-
Another group of states is characterized by hypoactiva- induced skin mast cell degranulation [28]. Chronic adminis-
tion of the stress system, rather than sustained activation, in tration of antalarmin is not associated with glucocorticoid
which chronically reduced secretion of CRH may result in deficiency and permits HPA axis and LC/NE responses to
pathological hypoarousal (Table 1) [25]. Patients with severe stress.
atypical, seasonal depression and the chronic fatigue syn- These data suggest that such CRH antagonists may be
drome fall in this category [46]. Similarly, patients with useful in human pathological states, such as melancholic
fibromyalgia have decreased urinary free cortisol excretion depression and chronic anxiety, associated with chronic
and frequently complain of fatigue. Hypothyroid patients hyperactivity of the stress system, along with predictable
also have clear evidence of CRH hyposecretion [28]. behavioral, neuroendocrine, metabolic and immune
Withdrawal from smoking has been associated with changes, based on the interrelations outlined above. Con-
decreased cortisol and catecholamine secretion [1]. De- versely, we will need potentiators of CRH secretion/action
creased CRH secretion in the early period of nicotine to treat atypical depression, postpartum depression and the
abstinence could explain the increased appetite and weight fibromyalgia/chronic fatigue syndromes, all characterized
gain frequently observed in these patients. In Cushing by low HPA axis and LC/NE activity, fatigue, depressive
syndrome, the clinical picture of atypical depression, hyper- symptomatology, hyperalgesia and increased immune/
phagia and weight gain, and fatigue and anergia is consistent inflammatory responses to stimuli.
with suppression of the CRH neuron by the associated
hypercortisolism. The periods after cure of hypercortisolism
or following cessation of chronic stress and the postpartum
period are also associated with atypical depression, sup- References
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